EP2144910B1 - Antibiotiques à base d'oxazolidinone - Google Patents

Antibiotiques à base d'oxazolidinone Download PDF

Info

Publication number
EP2144910B1
EP2144910B1 EP08737800.6A EP08737800A EP2144910B1 EP 2144910 B1 EP2144910 B1 EP 2144910B1 EP 08737800 A EP08737800 A EP 08737800A EP 2144910 B1 EP2144910 B1 EP 2144910B1
Authority
EP
European Patent Office
Prior art keywords
methyl
methoxy
oxazolidin
azetidin
naphthyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP08737800.6A
Other languages
German (de)
English (en)
Other versions
EP2144910A2 (fr
Inventor
Daniel Bur
Christian Hubschwerlen
Georg Rueedi
Jean-Philippe Surivet
Cornelia Zumbrunn Acklin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to EP15154086.1A priority Critical patent/EP2915813B1/fr
Priority to PL08737800T priority patent/PL2144910T3/pl
Priority to EP15154003.6A priority patent/EP2905283B1/fr
Publication of EP2144910A2 publication Critical patent/EP2144910A2/fr
Application granted granted Critical
Publication of EP2144910B1 publication Critical patent/EP2144910B1/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention concerns novel antibiotic derivatives, a pharmaceutical antibacterial composition containing them and the use of these compounds in the manufacture of a medicament for the treatment of infections (e.g. bacterial infections).
  • infections e.g. bacterial infections
  • These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram positive and Gram negative aerobic and anaerobic bacteria and mycobacteria.
  • Certain antibacterial agents are known from WO 2006/081289 , but these agents do not contain an oxazolidinone moiety. Further antibacterial agents are disclosed in WO 2002/050040 , but in these agents the piperazine ring is not directly bound to the quinoline analog moiety. Certain oxazolidinone derivatives having effects on the central nervous system are known from EP0300272 .
  • a bond interrupted by a wavy line shows the point of attachment of the radical drawn.
  • the radical drawn below is the 4 H -benzo[1,4]thiazin-3-on-6-yl group.
  • halogen refers to fluorine, chlorine, bromine or iodine; especially to fluorine, chlorine or bromine; preferably to fluorine or chlorine.
  • halogen as used for the substituents R a and R 1 preferably refers to fluorine.
  • alkyl refers to a straight or branched chain alkyl group containing one to four carbon atoms.
  • (C x -C y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms.
  • a (C 1 -C 4 )alkyl group contains from one to four carbon atoms.
  • Representative examples of alkyl groups include methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec -butyl and tert -butyl.
  • Preferred are methyl, ethyl, n -propyl and iso -propyl.
  • Most preferred are ethyl and methyl.
  • (C 2 -C 4 )alkyl which is mono- or di-substituted with hydroxy means a (C 2 -C 4 )alkyl group as defined before, wherein one or two hydrogen atoms have been replaced by hydroxy.
  • Examples of such groups are 2-hydroxyethyl, 3-hydroxypropyl, 1,3-dihydroxy-propan-2-yl and 2,3-dihydroxypropan-1-yl. Preferred is 2-hydroxyethyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • (C x -C y )alkoxy refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (C 1 -C 4 )alkoxy group contains from one to four carbon atoms.
  • Representative examples of alkoxy groups include methoxy, ethoxy, n -propoxy, iso -propoxy, n -butoxy, iso -butoxy, sec- butoxy and tert -butoxy. Preferred are ethoxy and methoxy. Most preferred is methoxy.
  • fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x -C y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a (C 1 -C 3 )fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • Representative examples of fluoroalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.
  • fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x -C y )fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (C 1 -C 3 )fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy and 2,2,2-trifluoroethoxy.
  • Preferred are (C 1 )fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy. Most preferred is trifluoromethoxy.
  • G representing "phenyl which is unsubstituted, mono-substituted in position 3 or 4, or disubstituted in positions 3 and 4", wherein the substituents are as defined for formula (I) and/or formula (IN), are selected from the group consisting of phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 4-bromo-3-fluoro-phenyl, 3,4-dimethoxy-phenyl, 4-fluoro-phenyl, 3-trifluoromethyl-phenyl, 3-chloro-4-fluoro-phenyl, 4-methyl-3-trifluoromethyl-phenyl, 4-(difluoromethoxy)-phenyl, 3-cyano-phenyl, 4-(pyrrolidin-1-yl)-phenyl, 3-methoxy-phenyl, 4-n-propyl-phenyl, 4-ethyl-phenyl, 3,4-dimethyl-phenyl,
  • a further example is 3-fluoro-phenyl.
  • Preferred groups are mono-substituted in position 3 or 4, or disubstituted in positions 3 and 4, wherein the substituents are as defined for formula (I) and/or formula (IN).
  • the substituents are independently selected from the group consisting of (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy and halogen.
  • Examples of G representing "pyridin-2-yl which is mono-substituted in position 5, wherein the substituent is selected from the group consisting of (C 1 -C 4 )alkyl and fluoroalkyl" are 3-methyl-pyridin-6-yl and 3-trifluoromethyl-pyridin-6-yl.
  • Such groups are the following groups [as used for the substituent G in formula (I P1 ), (I N-P1 ) and/or formula (I CE-P1 )], wherein G represents "a group selected from the group consisting of: wherein Q and Q' independently represent O or S".
  • Preferred examples of such groups are 2,3-dihydro-benzo[1,4]dioxin-6-yl, benzo[1,3]dioxol-5-yl, 3-oxo-3,4-dihydro-2 H- benzo[1,4]oxazin-6-yl, 3-oxo-3,4-dihydro-2 H -benzo[1,4]thiazin-6-yl, benzothiazol-6-yl and benzooxazol-6-yl.
  • R 2 representing (C 1 -C 4 )alkoxy-carbonyl is ethoxy-carbonyl.
  • Examples of -NR N1 R N2 groups are dimethylamino and pyrrolidin-1-yl.
  • the compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of formula (IN) and/or formula (I N-P1 ) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • Compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) are suitable for the use as chemotherapeutic active compounds in human and veterinary medicine and as substances for preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibres, leather, paper and wood.
  • These compounds according to the invention are particularly active against bacteria and bacteria-like organisms. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens as well as disorders related to bacterial infections comprising pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casseliflavus, S. epidermidis, S.
  • haemolyticus or Peptostreptococcus spp.
  • pharyngitis rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum
  • respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae
  • blood and tissue infections including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E.
  • faecium E. durans, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S.
  • Streptococcus pyogenes Streptococcus agalactiae, Streptococcal groups C-F (minute colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae
  • uncomplicated acute urinary tract infections related to infection by Staphylococcus aureus, coagulase-negative staphylococcal species, or Enterococcus spp.
  • urethritis and cervicitis sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae
  • aureus food poisoning and toxic shock syndrome
  • Groups A, B, and C streptococci ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H.
  • MAC Mycobacterium avium complex
  • chelonei gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease related to infection by Helicobacter pylori or Chlamydia pneumoniae.
  • Compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) are further useful for the preparation of a medicament for the treatment of infections that are mediated by bacteria such as E. coli, Klebsiella pneumoniae and other Enterobacteriaceae, Acinetobacter spp., Stenothrophomonas maltophilia, Neisseria meningitidis, Bacillus cereus, Bacillus anthracis, Clostridium difficile, Corynebacterium spp., Propionibacterium acnes and bacteroide spp.
  • bacteria such as E. coli, Klebsiella pneumoniae and other Enterobacteriaceae, Acinetobacter spp., Stenothrophomonas maltophilia, Neisseria meningitidis, Bacillus cereus, Bacillus anthracis, Clostridium difficile, Corynebacterium spp., Propionibacterium acne
  • Compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) are further useful to treat protozoal infections caused by Plasmodium malaria, Plasmodium falciparum, Toxoplasma gondii, Pneumocystis carinii, Trypanosoma brucei and Leishmania spp.
  • One aspect of this invention therefore relates to the use of a compound of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a bacterial infection.
  • bacterial infections can also be treated using compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry.
  • the present invention also relates to pharmacologically acceptable salts and to compositions and formulations of compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3).
  • any reference to a compound of formula (I N ) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
  • salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to " Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217 .
  • a pharmaceutical composition according to the present invention contains at least one compound of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics.
  • therapeutically useful agents that contain compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3), their salts and formulations thereof are also comprised in the scope of the present invention.
  • the compounds of formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins ]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Another aspect of the invention concerns a method for the prevention or the treatment of a bacterial infection in a patient comprising the administration to said patient of a pharmaceutically active amount of a compound according to formula (IN) and/or formula (I N-P1 ) according to embodiments 1) and/or 3), or a pharmaceutically acceptable salt thereof.
  • any preferences indicated for the compounds of formula (IN) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula formula (I N-P1 ).
  • the compounds of formula (I N ) and/or formula (I N-P1 ) according to embodiments 1) and/or 3) may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments or to make a room or an area aseptic.
  • the compounds of formula (IN) and/or formula (I N-P1 ) could be contained in a solution or in a spray formulation.
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
  • room temperature rt as used herein refers to a temperature of about 25°C.
  • Sections a) to f) hereafter describe general methods for preparing compounds of formula (I). The preparation of elaborated intermediates and basic building blocks is described thereafter. General synthetic methods used repeatedly throughout the schemes below are referenced to and described in the end of this section. If not indicated otherwise, the generic groups or integers U, V, W, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , R c , R d , R e , R f , R g , R h , A, B, D, E, G, m and n are as defined for formula (I). Other abbreviations used are defined in the experimental section.
  • the generic groups R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , R c , R d , R e , R f , R g , R h , A, B, D or E might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG).
  • protecting groups is well known in the art (see for example " Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999 ). For the purposes of this discussion, it will be assumed that such protecting groups as are necessary are in place.
  • the vinyl derivatives of formula (XIII) are transformed into the corresponding epoxides of formula (IV) either through direct epoxidation of the terminal double bond with a peracide such as mCPBA or H 2 O 2 in presence of an inorganic base such as NaOH, NaHCO 3 or urea or via cis-dihydroxylation with OsO 4 /NMO following [general synthetic method 9], or as described in Tetrahedron Lett. 1976, 23, 1973-76 , followed by conversion into the corresponding epoxides after mesylation or tosylation, and ring closure under basic conditions such as K 2 CO 3 or NaOMe.
  • a peracide such as mCPBA or H 2 O 2
  • an inorganic base such as NaOH, NaHCO 3 or urea
  • OsO 4 /NMO cis-dihydroxylation with OsO 4 /NMO following [general synthetic method 9], or as described in Tetrahedron Lett. 1976, 23, 1973-76
  • chiral epoxides In case chiral epoxides are required, they can be obtained by hydrolytic kinetic resolution (HKR) catalyzed by chiral (salen)-Co(III) complex (e.g . [( R , R )-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato(2-)]cobalt(III) of the racemic mixture of epoxides as described by Jacobsen et al in J. Am. Chem. Soc. 2002, 124, 1307-1315 and Science, 1997, 277, 936-938 .
  • HLR hydrolytic kinetic resolution
  • the chiral epoxides can also be obtained from the ethylenic derivatives of formula (XIII) through either Shi chiral epoxidation using a chiral ketone as described Acc. Chem Res. 2004, 37, 488-496 or through chiral cis-dihydroxylation using AD mixtures in presence of methanesulfonamide in a water/2-methyl-2-propanol mixture as described in Chem. Rev. 1994, 94, 2483 .
  • the epoxide of formula (IV) can also be obtained by reacting the amines of formula (XI) with epichlorhydrin, or optionally with one of the two enantiomers of epichlorhydrin, followed by protection of the amine function with a benzyloxycarbonyl or a tert -butoxycarbonyl group following [general synthetic method 1], epoxide formation after basic treatment and removal of the transient amino protecting group following [general synthetic method 10].
  • Acids of formula (XII) can be obtained by oxidation of either the corresponding alcohol of formula (XXVI) or of the aldehyde of formula (XXVII) following [general synthetic method 13].
  • Aldehydes of formula (XXVII) are obtained from alkenes of formula (XXIX) after tandem cis-dihydroxylation with OsO 4 and periodic cleavage, or, alternatively, from the corresponding alcohol of formula (XXVIII) following [general synthetic method 14].
  • Alkenes of formula (XXIX) are obtained from the known epoxides of formula (XXVIII) after ring opening with the amines of formula G-NH 2 , followed by oxazolidinone formation as described before.
  • Derivatives of formula (VII) wherein L 1 represents Li can be prepared from the corresponding derivatives of formula (VII) wherein L 1 represents Br after reaction with n- BuLi between -80°C and -30°C in a solvent such as THF or ether.
  • Amines are usually protected as carbamates such as Alloc, Cbz, BOC or FMOC. They are obtained by reacting the amine with allyl or benzyl chloroformate, di tert-butyl dicarbonate or FMOC-Cl in presence of a base such as NaOH, TEA, DMAP or imidazole. They can also be protected as N-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as sodium carbonate or TEA.
  • N -benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde and a borohydride reagent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 in a solvent such as MeOH, DCE or THF.
  • a borohydride reagent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 in a solvent such as MeOH, DCE or THF.
  • the alcohols are protected as silyl ether (usually TBDMS or TBDPS).
  • TBDMS silyl chloride reagent
  • TBDPS-Cl silyl chloride reagent
  • a base such as imidazole or TEA
  • a solvent such as DCM or DMF between +10°C and +40°C.
  • Further strategies to introduce other alcohol protecting groups have been described in Protecting Groups in Organic Synthesis 3rd Ed; 1999, 23-147; T.W.Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y .).
  • the silyl ether groups are removed either using fluoride anion sources such as tetrabutyl ammonium fluoride in THF between 0°C and +40°C or HF in MeCN between 0°C and +40°C or using acidic conditions such as AcOH in THF/MeOH or HCl in MeOH. Further methods to remove the TBDMS and TBDPS groups are given in Protecting Groups in Organic Synthesis 3rd Ed; 1999, 133-139 and 142-143 respectively; T.W.Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y .).
  • fluoride anion sources such as tetrabutyl ammonium fluoride in THF between 0°C and +40°C or HF in MeCN between 0°C and +40°C or using acidic conditions such as AcOH in THF/MeOH or HCl in MeOH.
  • the carbamate of formula (V) is reacted in a dry solvent such as THF with a strong organic base such as n-BuLi between -100°C and -30°C or with lithium or potassium tert -butoxide or KHMDS between -100°C and -30°C.
  • a dry solvent such as THF
  • a strong organic base such as n-BuLi between -100°C and -30°C or with lithium or potassium tert -butoxide or KHMDS between -100°C and -30°C.
  • the anion is reacted at these temperatures with the required epoxide and allowed to reach room temperature.
  • the aromatic halide or the triflate is reacted with the corresponding amine in presence of a palladium catalyst such as palladium (II) acetate, in presence of a ligand such as DPEphos and in presence of a base such as K 3 PO 4 , between +20°C and +100°C, as described in J. Org. Chem. 2007, 72, 2232-2235 .
  • a palladium catalyst such as palladium (II) acetate
  • a ligand such as DPEphos
  • a base such as K 3 PO 4
  • the reaction is performed between an aromatic halide or triflate and a lactam in presence of CuI, an inorganic base such as K 2 CO 3 or K 3 PO 4 between +40°C and +110°C, as described in Tetrahedron Letters 2006, 47, 1181-86 .
  • Grignard reagents are prepared by reacting the halide in a dry aprotic solvent such as THF or ether with magnesium. The reaction is initiated by the addition of a trace of I 2 .
  • Lithium reagents are prepared by reacting the halide in a dry aprotic solvent such as THF or ether with a butyl-lithium reagent. The resulting metal-organic reagent is reacted with the corresponding ketone between -80°C and +60°C in a dry aprotic solvent such as THF or ether.
  • the alcohol is reacted with Ms-Cl, Tf-Cl or Ts-Cl in presence of a base such as TEA in a dry aprotic solvent such as pyridine, THF or DCM between -30°C and +50°C.
  • a base such as TEA
  • a dry aprotic solvent such as pyridine, THF or DCM between -30°C and +50°C.
  • Tf 2 O or Ms 2 O can also be used.
  • These sulfonates can be reacted with sodium iodide in acetone or DMF between +40°C and +120°C delivering the corresponding iodo derivatives.
  • the alcohol reacts with an amine as described in [general synthetic method 11].
  • the carboxylic acid is reacted with the amine in presence of an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or di-( N -succinimidyl)-carbonate, in a dry aprotic solvent such as DCM, MeCN or DMF between -20°C and +60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p. 381 ).
  • an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or di-( N -succinimidyl)-carbonate
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between -20° and +60°C. Further activating agents can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section nitriles, carboxylic acids and derivatives p. 1941-1949 .
  • the diol is obtained by dihydroxylation of the corresponding ethylenic derivative using a catalytic amount of osmium tetroxide in the presence a co-oxidant such as NMO in aq. solvent such as an acetone - water or DCM - water mixture (see Cha, J.K. Chem. Rev. 1995, 95, 1761-1795 ).
  • the chiral cis-diols are obtained by using AD-mix ⁇ or AD-mix ⁇ in presence of methanesulfonamide in a water/2-methyl-2 propanol mixture as described in Chem. Rev. (1994), 94, 2483 .
  • the sense of induction relies on the chiral ligand contained in the AD mixture, either a dihydroquinine-based ligand in AD-mix ⁇ or a dihydroquinidine-based ligand in AD-mix ⁇ .
  • the benzyl carbamates are deprotected by hydrogenolysis over a noble catalyst (e.g. Pd/C or Pd(OH) 2 /C).
  • a noble catalyst e.g. Pd/C or Pd(OH) 2 /C.
  • the Boc group is removed under acidic conditions such as HCl in an organic solvent such as MeOH or dioxane, or TFA neat or diluted in a solvent such DCM.
  • Further general methods to remove amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3rd Ed (1999), 494-653; T.W. Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y .).
  • the amine derivative is reacted with a compound of formula alkyl-L 2 , wherein L 2 represents O-Ms, O-Tf, O-Ts, Cl, Br or I, a compound of formula (X) wherein L 2 represents O-Ms, O-Tf, O-Ts, Cl, Br or I, or an allyl- or homoallyl halogenide in presence of an inorganic base such as K 2 CO 3 or an organic base such as TEA in a solvent such as THF between 0°C and +80°C.
  • the ketal is converted into its corresponding ketone under acidic conditions such as diluted aq. HCl in MeOH, diluted aq. AcOH or by using an acidic resin such as Amberlite IR120H or DOWEX 50W8 in a water-solvent mixture such as MeOH/water or THF/water.
  • acidic conditions such as diluted aq. HCl in MeOH, diluted aq. AcOH or by using an acidic resin such as Amberlite IR120H or DOWEX 50W8 in a water-solvent mixture such as MeOH/water or THF/water.
  • Aldehydes can be oxidized into their corresponding acids by a variety of methods as described in Comprehensive Organic Transformations. A guide to Functionnal Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999 . Section nitriles, carboxylic acids and derivatives p.1653-1655. Among them, potassium permanganate in an acetone-water mixture (see Synthesis 1987, 85 ) or sodium chlorite in 2-methyl-2-propanol in presence of 2-methyl-2-butene (see Tetrahedron 1981, 37, 2091-2096 ) are frequently used.
  • Alcohols can be directly oxydized into their corresponding acids by a variety of methods as described in Comprehensive Organic Transformations. A guide to Functionnal Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999 . Section nitriles, carboxylic acids and derivatives p.1646-1648. Among them, [bis(acetoxy)iodo]benzene in presence of TEMPO, the Jones reagents (CrO 3 /H 2 SO 4 ), NaIO 4 in presence of RuCl 3 , KMnO 4 or pyridine H 2 Cr 2 O 7 are frequently used.
  • the alcohols can be transformed into their corresponding aldehydes through oxidation under Swern (see D. Swern et al., J. Org. Chem. 1978, 43, 2480-2482 ) or Dess Martin (see D.B. Dess and J.C. Martin, J. Org. Chem. 1983, 48, 4155 ) conditions, respectively
  • the esters can be transformed into their corresponding aldehydes by controlled reduction with a bulky hydride reagent such as DIBAH.
  • the hydrolysis is usually performed by treatment with an alkali hydroxide such as LiOH, KOH or NaOH in a water-dioxane or water - THF mixture between 0°C and +80°C.
  • an alkali hydroxide such as LiOH, KOH or NaOH
  • the hydrolysis can also be performed in neat TFA or diluted TFA or HCl in an organic solvent such as ether or THF.
  • the reaction is performed in presence of tetrakis(triphenylphosphine)palladium(0) in presence of an ⁇ -allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and +50°C in a solvent such as THF.
  • an ⁇ -allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and +50°C in a solvent such as THF.
  • the ester side chain is benzyl
  • the reaction is performed under hydrogen in presence of a noble metal catalyst such as Pd/C in a solvent such as MeOH, THF or EA.
  • the compounds of formula (IN) and/or formula (I N-P1 ) obtained according to the abovementioned general preparation methods may then, if desired, be converted into their salts, and notably into their pharmaceutically acceptable salts.
  • the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • LC-MS Sciex API 2000 with Agilent 1100 Binary Pump and DAD, using RP-C18 based columns
  • TLC TLC-plates from Merck, Silica gel 60 F 254
  • melting point Compounds are purified by chromatography on Silica gel 60A. NH 4 OH as used for CC is 25% aq. Racemates can be separated into their enantiomers as described before.
  • Preferred conditions of chiral HPLC are: ChiralPak AD (4.6x250mm, 5 ⁇ m) column, using an isocratic mixture (eg. at a ratio of 10/90) of eluent A (EtOH, in presence of diethylamine in an amount of eg. 0.1%) and eluent B (hexane), at rt, at a flow rate of eg. 0.8 mL/min.
  • the BOC protected amine (1 mmol) is dissolved in DCM (5 mL) and treated with TFA (2 mL). The mixture is stirred at rt for 1 h, concentrated in vacuo and taken up in DCM/aq. NH a OH. The org. layer is washed with water, dried over MgSO 4 and concentrated.
  • Example 1 ( S )-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-( ⁇ [1-(6-methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylmethyl]-amino ⁇ -methyl)-oxazolidin-2-one
  • step RE ii) the desired intermediate was isolated as yellow oil (0.24 g, 40%). MS (ESI, m/z): 336.8 [M+H + ].
  • Example 3 6-(( R )-5- ⁇ [1-(3-Fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H -benzo[1,4]oxazin-3-one
  • Example 6 6-(( R )-5- ⁇ [1-(3-Fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H -benzo[1,4]thiazin-3-one
  • Example 7 6-(( R )-5- ⁇ [1-(6-Methoxy-quinolin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H -benzo[1,4]thiazin-3-one
  • Example 10 6-(( R )-5- ⁇ [1-(6-Methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H -benzo[1,4]oxazin-3-one
  • Example 11 6-(( R )-5- ⁇ [1-(6-Methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H- benzo[1,4]thiazin-3-one
  • Example 12 6-(( R )-5- ⁇ [1-(6-Methoxy-quinazolin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H- benzo[1,4]oxazin-3-one
  • Example 13 6-(( R )-5- ⁇ [1-(6-Methoxy-quinazolin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H- benzo[1,4]thiazin-3-one
  • Example 14 6-[( R )-5-( ⁇ [1-(6-Methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-yl]-methyl-amino ⁇ -methyl)-2-oxo-oxazolidin-3-yl]-4 H -benzo[1,4]thiazin-3-one
  • Example 15 6-(( S )-5- ⁇ [1-(6-Methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H- benzo[1,4]thiazin-3-one
  • Example 17 6-[( S )-5-( ⁇ [1-(6-Methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylmethyl]-amino ⁇ -methyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one
  • Example 18 N -[1-(6-Methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-yl]-2-[( R )-2-oxo-3-(3-oxo-3,4-dihydro-2 H- benzo[1,4]thiazin-6-yl)-oxazolidin-5-yl]-acetamide
  • Example 20 ( S )-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-( ⁇ [1-(6-methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylmethyl]-methyl-amino ⁇ -methyl)-oxazolidin-2-one
  • Example 40 1-(6-Methoxy-[1,5]naphthyridin-4-yl)-azetidine-3-carboxylic acid [(R)-3-(3-fluoro-4-methyl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amide
  • Example 45 7-Fluoro-6-(( R )-5- ⁇ [1-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-azetidin-3-ylamino]-methyl ⁇ -2-oxo-oxazolidin-3-yl)-4 H -benzo[1,4]thiazin-3-one
  • Example 51 4-(3- ⁇ [(R)-2-Oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino ⁇ -azetidin-1-yl)-quinoline-6-carbonitrile

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Claims (14)

  1. Composé de formule (IN),
    Figure imgb0062
     où
    R1 représente un hydrogène, un alkoxy, un halogène ou un cyano ;
    un ou deux des radicaux U, V, W et X représente(nt) un N et les restants représentent chacun un CH ou, dans le cas de X, représente un CRa ;
    Ra représente un hydrogène ou un halogène ;
    R6 représente un hydrogène ou un (C1-C4)alkyle ;
    A représente un N ;
    ▪ B représente un CH, D représente un *-CO-NH-, où l'astérisque indique la liaison qui est rattachée à B, E représente un CH2, R2, R3, R4 et R5 représentent chacun un H et m et n représentent chacun le nombre entier 0 ; ou
    ▪ B représente un CH, D représente un *-CH2-N(Rf)-, où l'astérisque indique la liaison qui est rattachée à B, E représente un CH2, un CH2CH2 ou un CO, R2, R3, R4 et R5 représentent chacun un H, Rf représente un H ou un (C1-C4)alkyle et m et n représentent chacun le nombre entier 0 ; ou
    ▪ B représente un CH, D représente un NRg, E représente un CH2, un CH2CH2, un CO ou un *-COCH2-, où l'astérisque indique la liaison qui est rattachée à B, R2, R3, R4 et R5 représentent chacun un H, Rg représente un H, un (C1-C4)alkyle ou un (C2-C4)alkyle qui est mono- ou disubstitué par un hydroxy et m et n représentent chacun le nombre entier 0 ;
    G représente un phényle qui est non substitué, monosubstitué en position 3 ou 4 ou disubstitué en positions 3 et 4, chaque substituant étant indépendamment sélectionné dans le groupe consistant en un C1-C4)alkyle, un (C1-C4)alkoxy, un fluoroalkyle, un fluoroalkoxy, un cyano, un halogène et un -NRN1RN2 ; ou
    G représente un pyridin-2-yle qui est monosubstitué en position 5, le substituant étant sélectionné dans le groupe consistant en un (C1-C4)alkyle et un fluoroalkyle ; ou
    G représente un 6,7-dihydro-[1,4]dioxino[2,3-c]pyridazin-3-yle ; ou
    G représente un groupement sélectionné dans le groupe consistant en les suivants :
    Figure imgb0063
    Figure imgb0064
     où
    Rh représente un hydrogène ou un fluor ;
    M représente un CH ou un N et Q et Q' représentent indépendamment un O ou un S ; et
    RN1 et RN2 représentent indépendamment un (C1-C4)alkyle ou, avec l'azote qui les porte, forment un noyau pyrrolidine ;
    ou sel de celui-ci.
  2. Composé de formule (IN) selon la revendication 1 où
    R6 représente un hydrogène ;
    ▪ B représente un CH, D représente un *-CH2-N(Rf)-, où l'astérisque indique la liaison qui est rattachée à B, E représente un CH2, un CH2CH2 ou un CO, R2, R3, R4 et R5 représentent chacun un H, Rf représente un H ou un (C1-C4)alkyle et m et n représentent chacun le nombre entier 0 ; ou
    ▪ B représente un CH, D représente un NRg, E représente un CH2, un CH2CH2, un CO ou un *-COCH2-, où l'astérisque indique la liaison qui est rattachée à B, R2, R3, R4 et R5 représentent chacun un H, Rg représente un H, un (C1-C4)alkyle ou un 2-hydroxyéthyle et m et n représentent chacun le nombre entier 0 ; et
    G représente un phényle qui est non substitué, monosubstitué en position 3 ou 4 ou disubstitué en positions 3 et 4, chaque substituant étant indépendamment sélectionné dans le groupe consistant en un (C1-C4)alkyle, un (C1-C4)alkoxy, un fluoroalkyle, un fluoroalkoxy, un cyano, un halogène et un -NRN1RN2; ou
    G représente un pyridin-2-yle qui est monosubstitué en position 5, le substituant étant sélectionné dans le groupe consistant en un (C1-C4)alkyle et un fluoroalkyle ; ou
    G représente un 6,7-dihydro-[1,4]dioxino[2,3-c]pyridazin-3-yle ; ou
    G représente un groupement sélectionné dans le groupe consistant en les suivants :
    Figure imgb0065
     et
    Figure imgb0066
     où
    M représente un CH ou un N et Q et Q' représentent indépendamment un O ou un S ;
    ou sel de celui-ci.
  3. Composé de formule (IN) selon la revendication 1 qui est également un composé de formule (IN-P1),
    Figure imgb0067
     où
    R1 représente un alkoxy, un halogène ou un cyano ;
    un ou deux des radicaux U, V, W et X représente(nt) un N et les restants représentent chacun un CH ou, dans le cas de X, représente un CRa ;
    Ra représente un hydrogène ou un halogène ;
    A représente un N, B représente un CH, D représente un *-CH2-NH-, où l'astérisque indique la liaison qui est rattachée à B, E représente un CH2 ou un CO, R2 , R3 , R4 et R5 représentent chacun un H et m et n représentent chacun le nombre entier 0 ;
    G représente un phényle qui est non substitué, monosubstitué en position 3 ou 4 ou disubstitué en positions 3 et 4, chaque substituant étant indépendamment sélectionné dans le groupe consistant en un (C1-C4)alkyle, un (C1-C4)alkoxy, un fluoroalkyle, un fluoroalkoxy, un cyano, un halogène et un - NRN1RN2 ; ou
    G représente un pyridin-2-yle qui est monosubstitué en position 5, le substituant étant sélectionné dans le groupe consistant en un (C1-C4)alkyle et un fluoroalkyle ; ou
    G représente un groupement sélectionné dans le groupe consistant en les suivants :
    Figure imgb0068
     où
    Q et Q' représentent indépendamment un O ou un S ; et
    RN1 et RN2 représentent indépendamment un (C1-C4)alkyle ou, avec l'azote qui les porte, forment un noyau pyrrolidine ;
    ou sel de celui-ci.
  4. Composé de formule (IN) selon la revendication 1, où deux des radicaux U, W et X représentent un N et les restants et V représentent chacun un CH ou, dans le cas de X, représente un CRa, Ra représentant un hydrogène ou un fluor ;
    ou sel de celui-ci.
  5. Composé de formule (IN) selon la revendication 1, où A représente un N ; et
    ▪ B représente un CH, D représente un *-CH2-N(Rf)-, où l'astérisque indique la liaison qui est rattachée à B, E représente un CH2, un CH2CH2 ou un CO, R2 , R3 , R4 et R5 représentent chacun un H, Rf représente un H ou un (C1-C4)alkyle et m et n représentent chacun le nombre entier 0 ; ou
    ▪ B représente un CH, D représente un NRg, E représente un CH2, un CH2CH2 ou un CO, R2, R3, R4 et R5 représentent chacun un H, Rg représente un H, un (C1-C4)alkyle ou un 2-hydroxyéthyle et m et n représentent chacun le nombre entier 0 ;
    ou sel de celui-ci.
  6. Composé de formule (IN) selon l'une quelconque des revendications 1, 2, 4 ou 5, où E représente un CH2 ou un CH2CH2 ;
    ou sel de celui-ci.
  7. Composé de formule (IN) selon l'une quelconque des revendications 1 à 6, où G représente un phényle qui est monosubstitué en position 4 ou disubstitué en positions 3 et 4, chaque substituant étant indépendamment sélectionné dans le groupe consistant en un (C1-C3)alkyle, un (C1-C3)alkoxy, un fluoroalkyle, un fluoroalkoxy et un halogène ;
    ou sel de celui-ci.
  8. Composé de formule (IN) selon l'une quelconque des revendications 1, 2 ou 4 à 6, où G représente un 6,7-dihydro-[1,4]dioxino[2,3-c]pyridazin-3-yle ; ou
    G représente un groupement sélectionné dans le groupe consistant en les suivants :
    Figure imgb0069
    Figure imgb0070
     où
    M représente un CH ou un N et Q et Q' représentent indépendamment un O ou un S ; ou sel de celui-ci.
  9. Composé de formule (IN) selon l'une quelconque des revendications 1, 2 ou 4 à 6, où G représente un 2,3-dihydro-benzo[1,4]dioxin-6-yle, un 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yle, un 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yle, un 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yle ou un 2-oxo-l,2-dihydro-quinoléin-7-yle ; ou sel de celui-ci.
  10. Composé de formule (IN) selon la revendication 1, qui est sélectionné dans le groupe consistant en les suivants :
    (S)-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylméthyl]-amino}-méthyl)-oxazolidin-2-one ;
    [1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylméthyl]-amide de l'acide (S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-oxazolidin-5-carboxylique ;
    6-((R)-5-{[1-(3-Fluoro-6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]oxazin-3-one ;
    (R)-5-{[1-(3-Fluoro-6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-3-(3-fluoro-4-méthyl-phényl)-oxazolidin-2-one ;
    (R)-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-{[1-(3-fluoro-6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-oxazolidin-2-one ;
    6-((R)-5-{[1-(3-Fluoro-6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-((R)-5-{[1-(6-Méthoxy-quinoléin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    (R)-3-(3-Fluoro-4-méthyl-phényl)-5-{[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-oxazolidin-2-one ;
    (R)-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-{[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-oxazolidin-2-one ;
    6-((R)-5-{[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]oxazin-3-one;
    6-((R)-5-{[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-((R)-5-{[1-(6-Méthoxy-quinazolin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]oxazin-3-one ;
    6-((R)-5-{[1-(6-Méthoxy-quinazolin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-[(R)-5-({[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one ;
    6-((S)-5-{[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-(5-{2-[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-éthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-[(S)-5-({[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylméthyl]-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one ;
    N-[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-yl]-acétamide ;
    [1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-amide de l'acide (S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-oxazolidin-5-carboxylique ;
    (S)-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylméthyl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    6-[(R)-5-({[1-(3-Fluoro-6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]oxazin-3-one ;
    6-[(R)-5-({(2-Hydroxy-éthyl)-[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one ;
    [1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylméthyl]-amide de l'acide (S)-3-(3-fluoro-4-méthyl-phényl)-2-oxo-oxazolidin-5-carboxylique ;
    6-((R)-5-{[1-(6-Méthoxy-2-méthyl-quinoléin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    (R)-5-({[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-3-phényl-oxazolidin-2-one ;
    (R)-3-(4-Difluorométhoxy-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-5-({[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-3-(4-méthyl-3-trifluorométhyl-phényl)-oxazolidin-2-one ;
    (R)-3-(3-Chloro-4-fluoro-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-(4-Éthyl-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-(3,4-Diméthyl-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-5-({[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-3-(4-propyl-phényl)-oxazolidin-2-one ;
    (R)-3-(3-Diméthylamino-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-(4-Bromo-3-fluoro-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-(3-Bromo-4-méthyl-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-(4-Bromo-3-méthyl-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-Benzothiazol-6-yl-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-Benzo[1,3]dioxol-5-yl-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-Benzothiazol-5-yl-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-(3-Fluoro-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    [(R)-3-(3-Fluoro-4-méthyl-phényl)-2-oxo-oxazolidin-5-ylméthyl]-amide de l'acide 1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-carboxylique ;
    3-(3-Fluoro-4-méthyl-phényl)-5-(2-{[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylméthyl]-amino}-éthyl)-oxazolidin-2-one ;
    6-[(R)-5-({[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one ;
    (R)-3-(6,7-Dihydro-[1,4]dioxino[2,3-c]pyridazin-3-yl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-yl]-méthyl-amino}-méthyl)-oxazolidin-2-one ;
    (R)-3-(3-Fluoro-4-méthyl-phényl)-5-({[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylméthyl]-amino}-méthyl)-oxazolidin-2-one;
    7-Fluoro-6-((R)-5-{[1-(3-fluoro-6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-((R)-5-{[1-(6-Méthoxy-quinoléin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]oxazin-3-one ;
    6-((R)-5-{[1-(3-Méthoxy-quinoléin-5-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-((R)-5-{[1-(2-Méthoxy-quinoléin-8-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-((R)-5-{[1-(7-Fluoro-2-méthoxy-quinoléin-8-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    6-((R)-5-{[1-(6-Fluoro-quinoléin-4-yl)-azétidin-3-ylamino]-méthyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one ;
    4-(3-{[(R)-2-Oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylméthyl]-amino}-azétidin-1-yl)-quinoléin-6-carbonitrile ;
    6-[(R)-5-({[1-(2-Méthoxy-quinoléin-8-yl)-azétidin-3-ylméthyl]-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one ;
    6-[(R)-5-({[1-(3-Méthoxy-quinoléin-5-yl)-azétidin-3-ylméthyl]-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one ;
    (R)-5-{[1-(6-Méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-3-(4-méthoxy-phényl)-oxazolidin-2-one ;
    (R)-3-(4-Éthoxy-phényl)-5-{[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-oxazolidin-2-one ;
    (R)-3-(4-Difluorométhoxy-phényl)-5-{[1-(6-méthoxy-[1,5]naphtyridin-4-yl)-azétidin-3-ylamino]-méthyl}-oxazolidin-2-one ; et
    6-[(R)-5-({[1-(6-Méthoxy-quinoléin-4-yl)-azétidin-3-ylméthyl]-amino}-méthyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one.
    ou sel de celui-ci.
  11. En tant que médicament, composé de formule (IN) selon la revendication 1 ou sel pharmaceutiquement acceptable de celui-ci.
  12. Composition pharmaceutique contenant, comme principe actif, un composé de formule (IN) selon la revendication 1 ou un sel pharmaceutiquement acceptable de celui-ci et au moins un excipient inerte sur le plan thérapeutique.
  13. Utilisation d'un composé de formule (IN) selon la revendication 1, ou d'un sel pharmaceutiquement acceptable de celui-ci, dans la fabrication d'un médicament pour la prévention ou le traitement d'une infection bactérienne.
  14. Composé de formule (IN) selon l'une quelconque des revendications 1 à 10, ou sel pharmaceutiquement acceptable de celui-ci, pour une utilisation dans la prévention ou le traitement d'une infection bactérienne.
EP08737800.6A 2007-04-11 2008-04-11 Antibiotiques à base d'oxazolidinone Not-in-force EP2144910B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP15154086.1A EP2915813B1 (fr) 2007-04-11 2008-04-11 Antibiotiques de type oxazolidinone
PL08737800T PL2144910T3 (pl) 2007-04-11 2008-04-11 Antybiotyki oksazolidynonowe
EP15154003.6A EP2905283B1 (fr) 2007-04-11 2008-04-11 Antibiotiques oxazolidinone

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IB2007051290 2007-04-11
IB2007054587 2007-11-12
IB2007054768 2007-11-23
PCT/IB2008/051374 WO2008126034A2 (fr) 2007-04-11 2008-04-11 Antibiotiques à base d'oxazolidinone

Related Child Applications (4)

Application Number Title Priority Date Filing Date
EP15154003.6A Division EP2905283B1 (fr) 2007-04-11 2008-04-11 Antibiotiques oxazolidinone
EP15154003.6A Division-Into EP2905283B1 (fr) 2007-04-11 2008-04-11 Antibiotiques oxazolidinone
EP15154086.1A Division EP2915813B1 (fr) 2007-04-11 2008-04-11 Antibiotiques de type oxazolidinone
EP15154086.1A Division-Into EP2915813B1 (fr) 2007-04-11 2008-04-11 Antibiotiques de type oxazolidinone

Publications (2)

Publication Number Publication Date
EP2144910A2 EP2144910A2 (fr) 2010-01-20
EP2144910B1 true EP2144910B1 (fr) 2015-10-28

Family

ID=39682545

Family Applications (3)

Application Number Title Priority Date Filing Date
EP15154003.6A Not-in-force EP2905283B1 (fr) 2007-04-11 2008-04-11 Antibiotiques oxazolidinone
EP15154086.1A Active EP2915813B1 (fr) 2007-04-11 2008-04-11 Antibiotiques de type oxazolidinone
EP08737800.6A Not-in-force EP2144910B1 (fr) 2007-04-11 2008-04-11 Antibiotiques à base d'oxazolidinone

Family Applications Before (2)

Application Number Title Priority Date Filing Date
EP15154003.6A Not-in-force EP2905283B1 (fr) 2007-04-11 2008-04-11 Antibiotiques oxazolidinone
EP15154086.1A Active EP2915813B1 (fr) 2007-04-11 2008-04-11 Antibiotiques de type oxazolidinone

Country Status (16)

Country Link
US (1) US8217029B2 (fr)
EP (3) EP2905283B1 (fr)
JP (1) JP5427770B2 (fr)
KR (1) KR101495269B1 (fr)
CN (3) CN101679415B (fr)
AR (1) AR066013A1 (fr)
AU (1) AU2008238904B2 (fr)
BR (1) BRPI0809977A8 (fr)
CA (3) CA2679071C (fr)
CL (1) CL2008001002A1 (fr)
ES (3) ES2622961T3 (fr)
MX (3) MX351589B (fr)
PL (3) PL2915813T3 (fr)
RU (1) RU2470022C2 (fr)
TW (1) TWI411434B (fr)
WO (1) WO2008126034A2 (fr)

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008337096B2 (en) 2007-12-18 2013-10-17 Actelion Pharmaceuticals Ltd 5-aminocyclylmethyl-oxazolidin-2-one derivatives
KR101590202B1 (ko) 2008-02-20 2016-01-29 액테리온 파마슈티칼 리미티드 아자트리사이클 항생 화합물
AR070458A1 (es) 2008-02-22 2010-04-07 Actelion Pharmaceuticals Ltd Derivados de oxazolidina, una composicion farmaceutica que los contiene y su uso en la preparacion de un medicamento para el tratamiento de una infeccion bacteriana.
RU2011108008A (ru) 2008-08-04 2012-09-10 Актелион Фармасьютиклз Лтд (Ch) Производные трициклического алкиламинометилоксазолидинона
AR073774A1 (es) 2008-10-07 2010-12-01 Actelion Pharmaceuticals Ltd Compuestos antibioticos oxazolidinona triciclicos
CA2738775A1 (fr) * 2008-10-10 2010-04-15 Actelion Pharmaceuticals Ltd 2-benzothiophenyl- et 2-naphtyl-oxazolidinones et leurs analogues isosteres aza utilises comme agents antibacteriens
FR2945533B1 (fr) * 2009-05-12 2011-05-27 Sanofi Aventis Derives de cyclopenta°c!pyrrolyl-alkylcarbamates d'heterocycles a 5 chainons, leur preparation et leur application en therapeutique
EP2388260A1 (fr) * 2010-05-21 2011-11-23 Archimica GmbH Procédé de fabrication pour un inhibiteur d'un facteur de coagulation sanguine
JPWO2012108376A1 (ja) 2011-02-07 2014-07-03 第一三共株式会社 アミノ基含有ピロリジノン誘導体
US8916573B2 (en) 2011-08-11 2014-12-23 Actelion Pharmaceuticals Ltd. Quinazoline-2,4-dione derivatives
CA2854264A1 (fr) * 2011-11-08 2013-05-16 Actelion Pharmaceuticals Ltd Derives antibiotiques de 2-oxo-oxazolidin-3,5-diyle
DE102012006884A1 (de) 2012-04-04 2013-10-10 Merck Patent Gmbh Cyclische Amide als MetAP-2 Inhibitoren
TWI633087B (zh) 2012-06-13 2018-08-21 赫孚孟拉羅股份公司 新穎二氮雜螺環烷及氮雜螺環烷
EP2864322B1 (fr) 2012-06-20 2016-04-27 Novartis AG Modulateur de la voie d'activation du complément et ses utilisations
WO2014024056A1 (fr) 2012-08-06 2014-02-13 Daiichi Sankyo Company, Limited Dérivés de pyrrolidine possédant des propriétés antibactériennes
SI2900669T1 (sl) 2012-09-25 2019-12-31 F. Hoffmann-La Roche Ag Derivati heksahidropirolo(3,4-C)pirola in sorodne spojine kot zaviralci avtotaksina (ATX) in kot zaviralci tvorbe lizofosfatidne kisline (LPA) za zdravljenje npr. bolezni ledvic
CN103012389A (zh) * 2013-01-24 2013-04-03 中国药科大学 一种利伐沙班中间体的制备方法
AR095079A1 (es) 2013-03-12 2015-09-16 Hoffmann La Roche Derivados de octahidro-pirrolo[3,4-c]-pirrol y piridina-fenilo
SI3074400T1 (en) 2013-11-26 2018-03-30 F. Hoffmann-La Roche Ag Octahydro-cyclobut (1,2-c, 3,4-cy) dipyrrole derivatives as autoantaxine inhibitors
AU2015238541B2 (en) 2014-03-26 2019-09-19 F. Hoffmann-La Roche Ag Condensed [1,4]diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors
AU2015238537B2 (en) 2014-03-26 2019-08-01 F. Hoffmann-La Roche Ag Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors
AR102256A1 (es) 2014-10-15 2017-02-15 Actelion Pharmaceuticals Ltd Derivados biaromáticos básicos antibacterianos con sustitución de aminoalcoxi
MA41168A (fr) 2014-12-17 2017-10-24 Acraf Nouveaux composés antibactériens
MA41898A (fr) 2015-04-10 2018-02-13 Hoffmann La Roche Dérivés de quinazolinone bicyclique
PE20180479A1 (es) 2015-09-04 2018-03-07 Hoffmann La Roche Nuevos derivados de fenoximetilo
PE20180552A1 (es) 2015-09-24 2018-04-02 Hoffmann La Roche Nuevos compuestos biciclicos como inhibidores duales de atx/ca
MA42919A (fr) 2015-09-24 2018-08-01 Hoffmann La Roche Composés bicycliques utilisés en tant qu'inhibiteurs d'atx
JP6845230B2 (ja) 2015-09-24 2021-03-17 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ デュアルａｔｘ／ｃａ阻害剤としての新規な二環式化合物
RU2018114289A (ru) 2015-09-24 2019-10-24 Ф. Хоффманн-Ля Рош Аг Бициклические соединения в качестве ингибиторов аутотаксина (atx)
KR102703312B1 (ko) 2015-12-10 2024-09-05 브라코 이미징 에스.피.에이. 조영제
JP6896733B2 (ja) 2015-12-10 2021-06-30 ブラッコ・イメージング・ソシエタ・ペル・アチオニＢｒａｃｃｏ Ｉｍａｇｉｎｇ Ｓ．Ｐ．Ａ． 二量体造影剤
DK3889145T3 (da) 2015-12-17 2024-03-18 Merck Patent Gmbh 8-cyano-5-piperidino-quinoliner som TLR7/8-antagonister og anvendelser deraf til behandling af immunsygdomme
GB201602235D0 (en) * 2016-02-08 2016-03-23 Redx Pharma Plc Antibacterial compounds
US20210179636A1 (en) * 2016-02-08 2021-06-17 Redx Pharma Plc Antibacterial compounds
AU2017218556A1 (en) * 2016-02-08 2018-08-09 Redx Pharma Plc Heterocyclic compounds, in particular 2-oxo-4,4,5,5,6,6,7,7-octahydrobenzoxazole derivatives, and their use as antibacterial compounds
EP3442949B1 (fr) 2016-04-13 2022-06-08 Bracco Imaging S.p.A. Produits de contraste
BR112019000696A2 (pt) 2016-08-08 2019-04-24 Merck Patent Gmbh antagonistas de tlr7/8 e uso dos mesmos
JP7145156B2 (ja) 2016-12-12 2022-09-30 ブラッコ・イメージング・ソシエタ・ペル・アチオニ 二量体造影剤
TW201833120A (zh) 2017-02-17 2018-09-16 瑞士商愛杜西亞製藥有限公司 芳基噁唑啶酮抗生素化合物
CN110382484B (zh) 2017-03-16 2022-12-06 豪夫迈·罗氏有限公司 新的作为atx抑制剂的二环化合物
WO2018167001A1 (fr) 2017-03-16 2018-09-20 F. Hoffmann-La Roche Ag Composés hétérocycliques utiles en tant qu'inhibiteurs doubles d'atx/ca
EP4248968A3 (fr) * 2017-07-18 2023-12-06 Merck Patent GmbH Antagonistes de tlr7/8 et leurs utilisations
EP3717490B1 (fr) * 2017-11-29 2023-05-24 Bugworks Research, Inc. Composés hétérocycliques antibactériens et leurs synthèses
CN109265389B (zh) * 2018-08-31 2020-08-18 南京富润凯德生物医药有限公司 2-(氨基甲基)-1-氧杂-7-氮杂螺[3.5]壬烷衍生物、中间体及其制备方法

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3723797A1 (de) 1987-07-18 1989-01-26 Merck Patent Gmbh Oxazolidinone
KR950014567B1 (ko) 1991-08-01 1995-12-08 주식회사대웅제약 신규한 퀴놀론 카르복실산 유도체
DE19707628A1 (de) * 1997-02-26 1998-08-27 Merck Patent Gmbh Oxazolidinone
KR20010086163A (ko) 1999-01-07 2001-09-08 이곤 이 버그 우울증 치료용 아릴피페라지닐-사이클로헥실 인돌 유도체
HUP0300721A3 (en) 2000-07-26 2006-02-28 Smithkline Beecham Plc Aminopiperidine quinolines and their azaisosteric analogues with antibacterial activity, process for producing them, pharmaceutical compositions containing them and use thereof
GB0031086D0 (en) * 2000-12-20 2001-01-31 Smithkline Beecham Plc Medicaments
GB0112834D0 (en) 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
GB0112836D0 (en) * 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
TW200409637A (en) 2002-06-26 2004-06-16 Glaxo Group Ltd Compounds
DE10247233A1 (de) * 2002-10-10 2004-06-17 Morphochem AG Aktiengesellschaft für kombinatorische Chemie Neue Verbindungen, die Topoisomerase IV inhibieren
EP1567520B1 (fr) * 2002-12-04 2008-10-15 Glaxo Group Limited Quinoleines et derives nitrogenes de ces composes ainsi que leur utilisation en tant qu'agents antibacteriens
DE10316081A1 (de) 2003-04-08 2004-10-21 Morphochem AG Aktiengesellschaft für kombinatorische Chemie Neue Verbindungen mit antibakterieller Aktivität
US7160888B2 (en) 2003-08-22 2007-01-09 Warner Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia
FR2872164B1 (fr) * 2004-06-29 2006-11-17 Aventis Pharma Sa Derives de quinoleines-4-substituees, leur procede et intermediaires de preparation et les compositions pharmaceutiques qui les contiennent
EP1771456A2 (fr) * 2004-07-30 2007-04-11 Palumed SA Molecules hybrides qa ou q est une aminoquinoleine et a est un residu antibiotique, leur synthese et leurs utilisations en tant qu'agent antibacterien
CA2580621A1 (fr) 2004-09-24 2006-03-30 Actelion Pharmaceuticals Ltd Nouveaux antibiotiques bicycliques
WO2006081289A2 (fr) * 2005-01-25 2006-08-03 Glaxo Group Limited Agents antibacteriens
AR054608A1 (es) 2005-08-08 2007-06-27 Actelion Pharmaceuticals Ltd Derivados de oxazolidinona enlazados a quinolonas como antibacterianos
PL1954697T3 (pl) 2005-10-21 2010-07-30 Glaxo Group Ltd Peri skondensowane tricykliczne związki użyteczne jako środki przeciwbakteryjne
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
JP2009520779A (ja) 2005-12-22 2009-05-28 グラクソ グループ リミテッド 複素環化合物、その製造およびその抗菌剤としての使用
ES2345166T3 (es) 2006-03-23 2010-09-16 Actelion Pharmaceuticals Ltd. Derivados antibioticos del tipo de ciclohexil- o piperidinilcarboxamida.
EP2007377A4 (fr) 2006-04-06 2011-08-17 Glaxo Group Ltd Agents antibactériens
GB0613208D0 (en) 2006-07-03 2006-08-09 Glaxo Group Ltd Compounds

Also Published As

Publication number Publication date
PL2144910T3 (pl) 2016-04-29
MX351589B (es) 2017-10-20
EP2905283A1 (fr) 2015-08-12
ES2557172T3 (es) 2016-01-22
JP5427770B2 (ja) 2014-02-26
US20110039823A1 (en) 2011-02-17
RU2470022C2 (ru) 2012-12-20
EP2915813A1 (fr) 2015-09-09
CA2876878C (fr) 2017-07-11
CA2679071C (fr) 2016-06-07
KR101495269B1 (ko) 2015-02-26
CA2876879C (fr) 2017-11-28
CA2876879A1 (fr) 2008-10-23
EP2915813B1 (fr) 2017-02-01
BRPI0809977A8 (pt) 2017-12-26
CN102746296B (zh) 2015-10-28
CN101679415B (zh) 2013-07-31
AU2008238904B2 (en) 2013-11-28
CN102746296A (zh) 2012-10-24
CA2876878A1 (fr) 2008-10-23
ES2622961T3 (es) 2017-07-10
CN102746297A (zh) 2012-10-24
MX2009010642A (es) 2009-10-22
WO2008126034A3 (fr) 2008-12-31
KR20090130086A (ko) 2009-12-17
CN102746297B (zh) 2015-08-26
MX351590B (es) 2017-10-20
PL2905283T3 (pl) 2017-06-30
TW200848031A (en) 2008-12-16
JP2010523646A (ja) 2010-07-15
BRPI0809977A2 (pt) 2014-10-07
WO2008126034A2 (fr) 2008-10-23
CA2679071A1 (fr) 2008-10-23
AR066013A1 (es) 2009-07-15
RU2009141311A (ru) 2011-05-20
TWI411434B (zh) 2013-10-11
EP2905283B1 (fr) 2016-12-14
ES2618492T3 (es) 2017-06-21
PL2915813T3 (pl) 2017-07-31
US8217029B2 (en) 2012-07-10
AU2008238904A1 (en) 2008-10-23
CN101679415A (zh) 2010-03-24
CL2008001002A1 (es) 2008-10-17
EP2144910A2 (fr) 2010-01-20

Similar Documents

Publication Publication Date Title
EP2144910B1 (fr) Antibiotiques à base d'oxazolidinone
EP2254887B1 (fr) Dérivés d'oxazolidinone
EP2066678B1 (fr) Dérivés spiraniques antibiotiques
EP2346862B1 (fr) 2-benzothiophényl- et 2-naphtyl-oxazolidinones et leurs analogues isostères aza utilisés comme agents antibactériens
EP2321307B1 (fr) Dérivés d'alkylaminométhyloxazolidinone tricycliques
EP2245028B1 (fr) Dérivés 5-aminocyclylméthyloxazolidin-2-one

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20091111

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

17Q First examination report despatched

Effective date: 20120413

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20150528

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 757880

Country of ref document: AT

Kind code of ref document: T

Effective date: 20151115

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602008040890

Country of ref document: DE

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2557172

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20160122

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160128

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160228

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160229

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20160400160

Country of ref document: GR

Effective date: 20160414

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602008040890

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20160729

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160411

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: IDORSIA PHARMACEUTICALS LTD, CH

Free format text: FORMER OWNER: ACTELION PHARMACEUTICALS LTD., CH

Ref country code: DE

Ref legal event code: R082

Ref document number: 602008040890

Country of ref document: DE

Representative=s name: LEDERER & KELLER PATENTANWAELTE PARTNERSCHAFT , DE

Ref country code: DE

Ref legal event code: R081

Ref document number: 602008040890

Country of ref document: DE

Owner name: IDORSIA PHARMACEUTICALS LTD, CH

Free format text: FORMER OWNER: ACTELION PHARMACEUTICALS LTD., ALLSCHWIL, CH

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: IDORSIA PHARMACEUTICALS LTD

Effective date: 20171107

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20171026 AND 20171101

REG Reference to a national code

Ref country code: NL

Ref legal event code: PD

Owner name: IDORSIA PHARMACEUTICALS LTD; CH

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), ASSIGNMENT; FORMER OWNER NAME: ACTELION PHARMACEUTICALS LTD.

Effective date: 20171011

REG Reference to a national code

Ref country code: AT

Ref legal event code: PC

Ref document number: 757880

Country of ref document: AT

Kind code of ref document: T

Owner name: IDORSIA PHARMACEUTICALS LTD, CH

Effective date: 20171213

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

Owner name: IDORSIA PHARMACEUTICALS LTD, CH

Effective date: 20171226

REG Reference to a national code

Ref country code: BE

Ref legal event code: FP

Effective date: 20151209

Ref country code: BE

Ref legal event code: PD

Owner name: IDORSIA PHARMACEUTICALS LTD; CH

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), AFFECTATION / CESSION; FORMER OWNER NAME: ACTELION PHARMACEUTICALS LTD.

Effective date: 20170905

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20080411

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160430

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20180418

Year of fee payment: 11

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151028

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20180420

Year of fee payment: 11

Ref country code: CH

Payment date: 20180419

Year of fee payment: 11

Ref country code: ES

Payment date: 20180525

Year of fee payment: 11

Ref country code: IE

Payment date: 20180424

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20180420

Year of fee payment: 14

Ref country code: AT

Payment date: 20180419

Year of fee payment: 11

Ref country code: BE

Payment date: 20180418

Year of fee payment: 11

Ref country code: IT

Payment date: 20180423

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20180418

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20190325

Year of fee payment: 12

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 757880

Country of ref document: AT

Kind code of ref document: T

Effective date: 20151028

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20190403

Year of fee payment: 12

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602008040890

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20190501

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 757880

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190411

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20190430

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20190411

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190430

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190411

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190411

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190501

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190430

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190430

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190430

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191105

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190411

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190411

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20200831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190412

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200411

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200411